Oxidized low-density lipoprotein stimulates endothelin-1 release and mRNA expression from rat mesangial cells

Endothelin-1 (ET-1) may be involved in the development and progression of atherosclerosis. Furthermore, endothelin receptor blockade was shown to reduce the formation of atherosclerotic lesions in experimental studies. Another potent pro-atherosclerotic risk factor is oxidized low-density lipoprotein (oxLDL). Endothelial cells mediate the uptake of oxLDL by the recently identified lectin-like oxLDL receptor-1 (LOX-1), which accumulates in atherosclerotic lesions. In the present study, we analysed the effects of ET-1 on oxLDL uptake and LOX-1 expression in primary cultures of human umbilical vein endothelial cells (HUVEC). ET-1 stimulated uptake of oxLDL in HUVEC, which reached a maximum after 1h. In further studies, we found a similar induction of LOX-1 mRNA and protein expression in response to ET-1. The augmented oxLDL uptake and the increased LOX-1 expression in response to ET-1 are mediated by the endothelin receptor B. Our data support a new pathophysiological mechanism by which locally and systemically increased ET-1 levels, e.g. in hypertensive patients, could promote LOX-1-mediated oxLDL uptake in human endothelial cells. This mechanism could promote the development and progression of endothelial dysfunction and atherosclerosis. In addition, endothelin receptor blockade could be considered as a new anti-atherosclerotic therapeutic principle.

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Growth Hormone Increases Low-Density Lipoprotein Receptor and HMG-CoA Reductase mRNA Expression in Mesangial Cells

Nephron Experimental Nephrology ◽

10.1159/000070237 ◽

2003 ◽

Vol 93 (4) ◽

pp. e134-e140 ◽

Cited By ~ 6

Author(s):

Marcos O. Machado ◽

Rosario D.C. Hirata ◽

Mario H. Hirata ◽

Przemyslaw Hirszel ◽

Donald F. Sellitti ◽

...

Keyword(s):

Growth Hormone ◽

Mrna Expression ◽

Mesangial Cells ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Low Density ◽

Lipoprotein Receptor ◽

Density Lipoprotein Receptor ◽

Reductase Mrna ◽

Coa Reductase

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Endothelin-1 plus oxidized low-density lipoprotein, but neither alone, increase human monocyte adhesion to endothelial cells

Clinical Science ◽

10.1042/cs20010110 ◽

2001 ◽

Vol 101 (6) ◽

pp. 731 ◽

Cited By ~ 2

Author(s):

M. R. LANGENFELD ◽

S. NAKHLA ◽

A. K. DEATH ◽

W. JESSUP ◽

D. S. CELERMAJER

Keyword(s):

Endothelial Cells ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Human Monocyte ◽

Low Density ◽

Monocyte Adhesion ◽

Oxidized Low Density Lipoprotein ◽

Endothelin 1

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Endothelin-1 plus oxidized low-density lipoprotein, but neither alone, increase human monocyte adhesion to endothelial cells

Clinical Science ◽

10.1042/cs1010731 ◽

2001 ◽

Vol 101 (6) ◽

pp. 731-738 ◽

Cited By ~ 6

Author(s):

M.R. LANGENFELD ◽

S. NAKHLA ◽

A.K. DEATH ◽

W. JESSUP ◽

D.S. CELERMAJER

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Adhesion Molecule ◽

Oxidized Ldl ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Low Density ◽

Human Monocytes ◽

Oxidized Low Density Lipoprotein ◽

Endothelin 1

Endothelin-1 is a potent vasoconstrictor and mitogenic peptide that is implicated in the atherosclerosis of apolipoprotein E-deficient mice and may promote atherogenesis in humans. We hypothesized that endothelin-1 might promote the adhesion of monocytes to endothelial cells, a key early event in atherosclerosis. We investigated the adhesion of primary human monocytes (isolated by elutriation) to human umbilical vein endothelial cell cultures after incubation with endothelin-1 (0.1 and 0.01nM; approximately physiological concentrations), copper-oxidized low-density lipoprotein (LDL) (0.1mg/ml) and a combination of the two. After a 4h incubation with 0.1 or 0.01nM endothelin-1 combined with oxidized LDL, adhesion was increased to 120±4% (P < 0.001 compared with control) and 118±4% (P < 0.002) respectively, whereas neither substance alone increased adhesion (92-104% of control values; not significant). Neither endothelin receptor A blockade nor co-incubation with anti-fibronectin antibody inhibited the pro-adhesive effects of endothelin-1 plus oxidized LDL (115±7% and 115±3% of control compared with 120±4% respectively; not significant). Endothelial cell expression of intercellular adhesion molecule-1, vascular adhesion molecule-1 and E-selectin were unchanged throughout the experiment. Therefore physiological concentrations of endothelin-1 and oxidized LDL may act synergistically to increase the adhesion of human monocytes to endothelial cells, contributing in part to the observed pro-atherogenic effects of endothelin-1.

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